THEOPHYLLINE (ANHYDROUS)

Theophylline (anhydrous) extended-release tablets in a controlled-release system allows a 24-hour dosing interval for appropriate patients. Theophylline, USP is structurally classified as a methylxanthine. It occurs as a white, odorless, crystalline powder with a bitter taste. Anhydrous theophylline has the chemical name 1H-Purine-2,6-dione,3,7-dihydro-1,3-dimethyl-, and is represented by the following structural formula: The molecular formula of anhydrous theophylline is C 7 H 8 N 4 O 2 with a molecular weight of 180.17. Each extended-release tablet for oral administration, contains 400 mg or 600 mg of anhydrous theophylline. Inactive ingredients: glyceryl behenate, silicified microcrystalline cellulose, silicon dioxide, and magnesium stearate. Theophylline Structural Formula

Theophylline is indicated for the treatment of the symptoms and reversible airflow obstruction associated with chronic asthma and other chronic lung diseases, e.g., emphysema and chronic bronchitis.

Theophylline (anhydrous) extended-release tablets 400 mg or 600 mg can be taken once a day in the morning or evening. It is recommended that theophylline (anhydrous) extended-release tablets be taken with meals. Patients should be advised that if they choose to take theophylline (anhydrous) extended-release tablets with food it should be taken consistently with food and if they take it in a fasted condition it should routinely be taken fasted. It is important that the product whenever dosed be dosed consistently with or without food. Theophylline (anhydrous) extended-release tablets are not to be chewed or crushed because it may lead to a rapid release of theophylline with the potential for toxicity. The scored tablet may be split. Infrequently, patients receiving theophylline (anhydrous) extended-release tablets 400 mg or 600 mg may pass an intact matrix tablet in the stool or via colostomy. These matrix tablets usually contain little or no residual theophylline. Stabilized patients, 12 years of age or older, who are taking an immediate-release or extended-release theophylline product may be transferred to once-daily administration of 400 mg or 600 mg theophylline (anhydrous) extended-release tablets on a mg-for-mg basis It must be recognized that the peak and trough serum theophylline levels produced by the once-daily dosing may vary from those produced by the previous product and/or regimen. General Considerations The steady-state peak serum theophylline concentration is a function of the dose, the dosing interval, and the rate of theophylline absorption and clearance in the individual patient. Because of marked individual differences in the rate of theophylline clearance, the dose required to achieve a peak serum theophylline concentration in the 10 to 20 mcg/mL range varies 4-fold among otherwise similar patients in the absence of factors known to alter theophylline clearance (e.g., 400 to 1600 mg/day in adults < 60 years old and 10 to 36 mg/kg/day in children 1 to 9 years old). For a given population there is no single theophylline dose that will provide both safe and effective serum concentrations for all patients. Administration of the median theophylline dose required to achieve a therapeutic serum theophylline concentration in a given population may result in either sub-therapeutic or potentially toxic serum theophylline concentrations in individual patients. For example, at a dose of 900 mg/d in adults < 60 years or 22 mg/kg/d in children 1 to 9 years, the steady-state peak serum theophylline concentration will be < 10 mcg/mL in about 30% of patients, 10 to 20 mcg/mL in about 50% and 20 to 30 mcg/mL in about 20% of patients. The dose of theophylline must be individualized on the basis of peak serum theophylline concentration measurements in order to achieve a dose that will provide maximum potential benefit with minimal risk of adverse effects. Transient caffeine-like adverse effects and excessive serum concentrations in slow metabolizers can be avoided in most patients by starting with a sufficiently low dose and slowly increasing the dose, if judged to be clinically indicated, in small increments (see Table V). Dose increases should only be made if the previous dosage is well tolerated and at intervals of no less than 3 days to allow serum theophylline concentrations to reach the new steady-state. Dosage adjustment should be guided by serum theophylline concentration measurement (see PRECAUTIONS, Laboratory Tests and DOSAGE AND ADMINISTRATION , Table VI). Healthcare providers should instruct patients and caregivers to discontinue any dosage that causes adverse effects, to withhold the medication until these symptoms are gone and to then resume therapy at a lower, previously tolerated dosage (see WARNINGS ). If the patient’s symptoms are well controlled, there are no apparent adverse effects, and no intervening factors that might alter dosage requirements (see WARNINGS and PRECAUTIONS ), serum theophylline concentrations should be monitored at 6 month intervals for rapidly growing children and at yearly intervals for all others. In acutely ill patients, serum theophylline concentrations should be monitored at frequent intervals, e.g., every 24 hours. Theophylline distributes poorly into body fat, therefore, mg/kg dose should be calculated on the basis of ideal body weight. Table V contains theophylline dosing titration schema recommended for patients in various age groups and clinical circumstances. Table VI contains recommendations for theophylline dosage adjustment based upon serum theophylline concentrations. Application of these general dosing recommendations to individual patients must take into account the unique clinical characteristics of each patient. In general, these recommendations should serve as the upper limit for dosage adjustments in order to decrease the risk of potentially serious adverse events associated with unexpected large increases in serum theophylline concentration. Table V. Dosing Initiation and Titration (as Anhydrous Theophylline). * Children (12 to 15 years) and Adults (16 to 60 years) without Risk Factors for Impaired Clearance. Titration Step Children < 45 kg Children > 45 kg and Adults 1. Starting Dosage 12 to 14 mg/kg/day up to a maximum of 300 mg/day admin. QD * 300 to 400 mg/day If caffeine-like adverse effects occur, then consideration should be given to a lower dose and titrating the dose more slowly (see ADVERSE REACTIONS). admin. QD * 2. After 3 days, if tolerated , increase dose to: 16 mg/kg/day up to a maximum of 400 mg/day admin. QD * 400 to 600 mg/day admin. QD * 3. After 3 more days, if tolerated , and if needed increase dose to: 20 mg/kg/day up to a maximum of 600 mg/day admin. QD * As with all theophylline products, doses greater than 600 mg should be titrated according to blood level (see Table VI). Patients with Risk Factors for Impaired Clearance, the Elderly (> 60 Years), and Those in Whom It Is Not Feasible to Monitor Serum Theophylline Concentrations: In children 12 to 15 years of age, the theophylline dose should not exceed 16 mg/kg/day up to a maximum of 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations. In adolescents ≥ 16 years and adults, including the elderly, the theophylline dose should not exceed 400 mg/day in the presence of risk factors for reduced theophylline clearance (see WARNINGS ) or if it is not feasible to monitor serum theophylline concentrations. * Patients with more rapid metabolism clinically identified by higher than average dose requirements, should receive a smaller dose more frequently (every 12 hours) to prevent breakthrough symptoms resulting from low trough concentrations before the next dose. Table VI. Dosage Adjustment Guided by Serum Theophylline Concentration. Peak Serum Concentration Dosage Adjustment < 9.9 mcg/mL If symptoms are not controlled and current dosage is tolerated, increase dose about 25%. Recheck serum concentration after three days for further dosage adjustment. 10 to 14.9 mcg/mL If symptoms are controlled and current dosage is tolerated, maintain dose and recheck serum concentration at 6 to 12 month intervals. Dose reduction and/or serum theophylline concentration measurement is indicated whenever adverse effects are present physiologic abnormalities that can reduce theophylline clearance occur (e.g., sustained fever), or a drug that interacts with theophylline is added or discontinued (see WARNINGS). If symptoms are not controlled and current dosage is tolerated consider adding additional medication(s) to treatment regimen. 15 to 19.9 mcg/mL Consider 10% decrease in dose to provide greater margin of safety even if current dosage is tolerated. 20 to 24.9 mcg/mL Decrease dose by 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. 25 to 30 mcg/mL Skip next dose and decrease subsequent doses at least 25% even if no adverse effects are present. Recheck serum concentration after 3 days to guide further dosage adjustment. If symptomatic, consider whether overdose treatment is indicated (see recommendations for chronic overdosage). > 30 mcg/mL Treat overdose as indicated (see recommendations for chronic overdosage). If theophylline is subsequently resumed, decrease dose by at least 50% and recheck serum concentration after 3 days to guide further dosage adjustment.

Theophylline (anhydrous) extended-release tablets are contraindicated in patients with a history of hypersensitivity to theophylline or other components in the product.

Adverse reactions associated with theophylline are generally mild when peak serum theophylline concentrations are < 20 mcg/mL and mainly consist of transient caffeine-like adverse effects such as nausea, vomiting, headache and insomnia. When peak serum theophylline concentrations exceed 20 mcg/mL, however, theophylline produces a wide range of adverse reactions including persistent vomiting, cardiac arrhythmias, and intractable seizures which can be lethal (see OVERDOSAGE ). The transient caffeine-like adverse reactions occur in about 50% of patients when theophylline therapy is initiated at doses higher than recommended initial doses (e.g., > 300 mg/day in adults and > 12 mg/kg/day in children beyond > 1 year of age). During the initiation of theophylline therapy, caffeine-like adverse effects may transiently alter patient behavior, especially in school age children, but this response rarely persists. Initiation of theophylline therapy at a low dose with subsequent slow titration to a predetermined age-related maximum dose will significantly reduce the frequency of these transient adverse effects (see DOSAGE AND ADMINISTRATION , Table V). In a small percentage of patients (< 3% of children and < 10% of adults) the caffeine-like adverse effects persist during maintenance therapy, even at peak serum theophylline concentrations within the therapeutic range (i.e., 10 to 20 mcg/mL). Dosage reduction may alleviate the caffeine-like adverse effects in these patients, however, persistent adverse effects should result in a reevaluation of the need for continued theophylline therapy and the potential therapeutic benefit of alternative treatment. Other adverse reactions that have been reported at serum theophylline concentrations < 20 mcg/mL include abdominal pain, agitation, anaphylactic reaction, anaphylactiod reaction, anxiety, cardiac arrhythmias, diarrhea, dizziness, fine skeletal muscle tremors, gastric irritation, gastroesophageal reflux, hyperuricemia, irritability, palpitations, pruritus, rash, sinus tachycardia, restlessness, transient diuresis, urinary retention and urticaria. In patients with hypoxia secondary to COPD, multifocal atrial tachycardia and flutter have been reported at serum theophylline concentrations ≥ 15 mcg/mL. There have been a few isolated reports of seizures at serum theophylline concentrations < 20 mcg/mL in patients with an underlying neurological disease or in elderly patients. The occurrence of seizures in elderly patients with serum theophylline concentrations < 20 mcg/mL may be secondary to decreased protein binding resulting in a larger proportion of the total serum theophylline concentration in the pharmacologically active unbound form. The clinical characteristics of the seizures reported in patients with serum theophylline concentrations < 20 mcg/mL have generally been milder than seizures associated with excessive serum theophylline concentrations resulting from an overdose (i.e., they have generally been transient, often stopped without anticonvulsant therapy, and did not result in neurological residua). Table IV. Manifestations of Theophylline Toxicity. These data are derived from two studies in patients with serum theophylline concentrations > 30 mcg/mL. In the first study (Study #1 - Shanon, Ann Intern Med 1993;119:1161-67), data were prospectively collected from 249 consecutive cases of theophylline toxicity referred to a regional poison center for consultation. In the second study (Study #2 - Sessler, Am J Med 1990;88:567-76), data were retrospectively collected from 116 cases with serum theophylline concentrations > 30 mcg/mL among 6000 blood samples obtained for measurement of serum theophylline concentrations in three emergency departments. Differences in the incidence of manifestations of theophylline toxicity between the two studies may reflect sample selection as a result of study design (e.g., in Study #1, 48% of the patients had acute intoxications versus only 10% in Study #2) and different methods of reporting results. Percentage of Patients Reported with Sign or Symptom Acute Overdose (Large Single Ingestion) Chronic Overdosage (Multiple Excessive Doses) Sign/Symptom Study 1 (n = 157) Study 2 (n = 14) Study 1 (n = 92) Study 2 (n = 102) Asymptomatic NR NR = Not reported in a comparable manner. 0 NR 6 Gastrointestinal Vomiting 73 93 30 61 Abdominal Pain NR 21 NR 12 Diarrhea NR 0 NR 14 Hematemesis NR 0 NR 2 Metabolic/Other Hypokalemia 85 79 44 43 Hyperglycemia 98 NR 18 NR Acid/base disturbance 34 21 9 5 Rhabdomyolysis NR 7 NR 0 Cardiovascular Sinus tachycardia 100 86 100 62 Other supraventricular tachycardias 2 21 12 14 Ventricular premature beats 3 21 10 19 Atrial fibrillation or flutter 1 NR 12 NR Multifocal atrial tachycardia 0 NR 2 NR Ventricular arrhythmias with hemodynamic instability 7 14 40 0 Hypotension/shock NR 21 NR 8 Neurologic Nervousness NR 64 NR 21 Tremors 38 29 16 14 Disorientation NR 7 NR 11 Seizures 5 14 14 5 Death 3 21 10 4

Adding a drug that inhibits theophylline metabolism (e.g., cimetidine, erythromycin, tacrine) or stopping a concurrently administered drug that enhances theophylline metabolism (e.g., carbamazepine, rifampin). (see PRECAUTIONS, Drug Interactions , Table II). When Signs or Symptoms of Theophylline Toxicity Are Present Whenever a patient receiving theophylline develops nausea or vomiting, particularly repetitive vomiting, or other signs or symptoms consistent with theophylline toxicity (even if another cause may be suspected), additional doses of theophylline should be withheld and a serum theophylline concentration measured immediately . Patients should be instructed not to continue any dosage that causes adverse effects and to withhold subsequent doses until the symptoms have resolved, at which time the healthcare professional may instruct the patient to resume the drug at a lower dosage (see DOSAGE AND ADMINISTRATION, Dosing Guidelines , Table VI). Drug Interactions Theophylline interacts with a wide variety of drugs. The interaction may be pharmacodynamic, i.e., alterations in the therapeutic response to theophylline or another drug or occurrence of adverse effects without a change in serum theophylline concentration. More frequently, however, the interaction is pharmacokinetic, i.e., the rate of theophylline clearance is altered by another drug resulting in increased or decreased serum theophylline concentrations. Theophylline only rarely alters the pharmacokinetics of other drugs. The drugs listed in Table II have the potential to produce clinically significant pharmacodynamic or pharmacokinetic interactions with theophylline. The information in the “Effect” column of Table II assumes that the interacting drug is being added to a steady-state theophylline regimen. If theophylline is being initiated in a patient who is already taking a drug that inhibits theophylline clearance (e.g., cimetidine, erythromycin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be smaller. Conversely, if theophylline is being initiated in a patient who is already taking a drug that enhances theophylline clearance (e.g., rifampin), the dose of theophylline required to achieve a therapeutic serum theophylline concentration will be larger. Discontinuation of a concomitant drug that increases theophylline clearance will result in accumulation of theophylline to potentially toxic levels, unless the theophylline dose is appropriately reduced. Discontinuation of a concomitant drug that inhibits theophylline clearance will result in decreased serum theophylline concentrations, unless the theophylline dose is appropriately increased. The drugs listed in Table III have either been documented not to interact with theophylline or do not produce a clinically significant interaction (i.e., < 15% change in theophylline clearance). The listing of drugs in Table II and III are current as of February 9, 1995. New interactions are continuously being reported for theophylline, especially with new chemical entities. The healthcare professional should not assume that a drug does not interact with theophylline if it is not listed in Table II. Before addition of a newly available drug in a patient receiving theophylline, the package insert of the new drug and/or the medical literature should be consulted to determine if an interaction between the new drug and theophylline has been reported. Table II. Clinically Significant Drug Interactions with Theophylline Refer to PRECAUTIONS, Drug Interactions for further information regarding table. . Drug Type of Interaction Effect Average effect on steady-state theophylline concentration or other clinical effect for pharmacologic interactions. Individual patients may experience larger changes in serum theophylline concentration than the value listed. Adenosine Theophylline blocks adenosine receptors. Higher doses of adenosine may be required to achieve desired effect. Alcohol A single large dose of alcohol (3 mL/kg of whiskey) decreases theophylline clearance for up to 24 hours. 30% increase Allopurinol Decreases theophylline clearance at allopurinol doses ≥ 600 mg/day. 25% increase Aminoglutethimide Increases theophylline clearance by induction of microsomal enzyme activity. 25% decrease Carbamazepine Similar to aminoglutethimide. 30% decrease Cimetidine Decreases theophylline clearance by inhibiting cytochrome P450 1A2. 70% increase Ciprofloxacin Similar to cimetidine. 40% increase Clarithromycin Similar to erythromycin. 25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression. Disulfiram Decreases theophylline clearance by inhibiting hydroxylation and demethylation. 50% increase Enoxacin Similar to cimetidine. 300% increase Ephedrine Synergistic CNS effects. Increased frequency of nausea, nervousness, and insomnia. Erythromycin Erythromycin metabolite decreases theophylline clearance by inhibiting cytochrome P450 3A3. 35% increase. Erythromycin steady-state serum concentrations decrease by a similar amount. Estrogen Estrogen containing oral contraceptives decrease theophylline clearance in a dose-dependent fashion. The effect of progesterone on theophylline clearance is unknown. 30% increase Flurazepam Similar to diazepam. Similar to diazepam. Fluvoxamine Similar to cimetidine. Similar to cimetidine. Halothane Halothane sensitizes the myocardium to catecholamines, theophylline increases release of endogenous catecholamines. Increased risk of ventricular arrhythmias. Interferon, human recombinant alpha-A Decreased theophylline clearance. 100% increase Isoproterenol (IV) Increases theophylline clearance. 20% decrease Ketamine Pharmacologic May lower theophylline seizure threshold. Lithium Theophylline increases renal lithium clearance. Lithium dose required to achieve a therapeutic serum concentration increased an average of 60%. Lorazepam Similar to diazepam. Similar to diazepam. Methotrexate (MTX) Decreases theophylline clearance. 20% increase after low dose MTX, higher dose MTX may have a greater effect. Mexiletine Similar to disulfiram. 80% increase Midazolam Similar to diazepam. Similar to diazepam. Moricizine Increases theophylline clearance. 25% decrease Pancuronium Theophylline may antagonize non-depolarizing neuromuscular blocking effects; possibly due to phosphodiesterase inhibition. Larger dose of pancuronium may be required to achieve neuromuscular blockade. Pentoxifylline Decreases theophylline clearance. 30% increase Phenobarbital (PB) Similar to aminoglutethimide. 25% decrease after 2 weeks of concurrent PB. Phenytoin Phenytoin increases theophylline clearance by increasing microsomal enzyme activity. Theophylline decreases phenytoin absorption. Serum theophylline and phenytoin concentrations decrease about 40%. Propafenone Decreases theophylline clearance and pharmacologic interaction. 40% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Propranolol Similar to cimetidine and pharmacologic interaction. 100% increase. Beta-2 blocking effect may decrease efficacy of theophylline. Rifampin Increases theophylline clearance by increasing cytochrome P450 1A2 and 3A3 activity. 20% to 40% decrease St. John’s Wort (Hypericum Perforatum) Decrease in theophylline plasma concentrations. Higher doses of theophylline may be required to achieve desired effect. Stopping St. John’s Wort may result in theophylline toxicity. Sulfinpyrazone Increases theophylline clearance by increasing demethylation and hydroxylation. Decreases renal clearance of theophylline. 20% decrease Tacrine Similar to cimetidine, also increases renal clearance of theophylline. 90% increase Thiabendazole Decreases theophylline clearance. 190% increase Ticlopidine Decreases theophylline clearance. 60% increase Troleandomycin Similar to erythromycin. 33% to 100% increase depending on troleandomycin dose. Verapamil Similar to disulfiram. 20% increase Table III. Drugs that Have Been Documented Not to Interact with Theophylline or Drugs that Produce No Clinically Significant Interaction with Theophylline. Refer to PRECAUTIONS, Drug Interactions for information regarding table. albuterol, systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, with or without methylprednisolone sulbactam metronidazole atenolol metoprolol azithromycin nadolol caffeine, dietary ingestion nifedipine cefaclor nizatidine co-trimoxazole (trimethoprim and norfloxacin sulfamethoxazole) ofloxacin diltiazem omeprazole dirithromycin prednisone, prednisolone enflurane ranitidine famotidine rifabutin felodipine roxithromycin finasteride sorbitol (purgative doses do not inhibit hydrocortisone theophylline absorption) isoflurane sucralfate isoniazid terbutaline, systemic isradipine terfenadine influenza vaccine tetracycline ketoconazole tocainide lomefloxacin